Neurodegenerative disorders, particularly late onset brain disorders diseases affect an increasing number of individuals in the aging society of developed countries. Alzheimer's disease (AD) and Parkinson disease are the most prevalent diseases, but Creutzfeldt-Jacob disease (CJD), ALS and others are also increasingly diagnosed. Subjects suffering from multiple sclerosis (MS), a brain disease affecting many millions, also develop over the years features of neurodegenerative conditions.
In addition to individual features of brain diseases, such as demyelination in multiple sclerosis or misfolding and aggregation of designated proteins such as PrPSc in prion diseases (CJD in humans), there are several common denominators in all these conditions in the form of sensitivity to oxidative stress (Butterfield D A and Kanski J. 2001. Mech Ageing Dev 122:945-962). It was shown recently that brain lipids in the MS lesions are oxidized (Haider L et al., 2001. Brain 134:1914-1924), and this may also be the case for other neurodegenerative conditions (Uttara B et al., 2009. Curr Neuropharmacol 7:65-74). In MS, oxidation of lipids in the myelin sheet may be an important factor in the demyelination process, since changes in the lipid layer may result in the decompression and subsequent release of Myelin basic protein and other components from their membrane location. In the case of genetic CJD, a mutation in PrP, a copper binding glycosylphosphatidylinositol (GPI) anchored membrane glycoprotein, which changes the PrP conformation, is the main cause for disease progression. It has recently been shown that the mutated PrP is oxidized in its Methionine residues (Canello T et al., 2010. PLoS Pathog 2010, 6 (7):e1000977). Proteins damaged by oxidation are also associated with Alzheimer disease (oxidation of amyloid-β, Aβ), Parkinson disease (oxidation of synuclein) and the aging process in general (Stadtman E R 2001. Ann N Y Acad Sci 928:22-38).
Most of the neurodegenerative diseases are of slow progression, and thus a long term economic effort is required for the medical system to cope with the patient's management. For some of these diseases no treatment of any kind is available while for others, partial treatment with severe side effects is being implemented. Thus, there is an ongoing search for effective and safe medications, including from natural sources.
Pomegranate (Punica granatum) has long been recognized as a fruit with many benefits for health. For example, pomegranate is known as the richest plant source of the female steroid hormone estrone and recently, the male hormone testosterone and another female steroid, estriol, have also been discovered in pomegranate seed oil. A wide range of polyphenolic compounds including flavonoids, anthocyanins and tannins have been characterized both in pomegranate juice and pericarp. Further, these polyphenols, extracted both from the fermented juice and the oil, have been shown to be potent antioxidant in vitro and to additionally inhibit the eicosanoid enzyme lipoxygenase. Polyphenols extracted from pomegranate seed oil have also been shown to be significantly inhibitory of another eicosanoid pathway enzyme, cyclooxygenase (Schubert S Y et al., 1999. J Ethnopharmacology 66 (1):11-17).
U.S. Application Publication No. 20020012710 discloses a cancer chemo-preventive mixture of a pomegranate seed oil product and a pomegranate juice product and a pharmaceutical composition containing same. According to some disclosed embodiments, a pomegranate peel product is further included. Further disclosed are a selective estrogen receptor modulator and other biologically active compounds derived from pomegranates as well as methods of use thereof.
International Application Publication No. WO 2005/070412 discloses a method of enhancing the immune response of an animal, including mammals and humans, to prevent or ameliorate immunoinflammatory diseases such as Inflammatory Bowel Disease (IBD), to increase immune system development, to maintain or increase CD4+ and CD8+ T lymphocyte levels, to increase immune function, to increase immune response against viruses and to prevent or ameliorate the Metabolic Syndrome, Type 2 diabetes and obesity by administering orally or parentally a therapeutically effective amount of punicic acid to the animal.
International Application Publication No. WO 2009/016620 discloses methods of producing pomegranate sprouts and pomegranate sprout preparation as well as food or feed products comprising same. The pomegranate sprouts and preparations may be consumed for general health, but may be especially advantage to subjects susceptible to conditions associated with oxidative stress, such as artherosclerosis, diabetes, cancer, cardiovascular disease, liver disease and individuals at risk of developing neurodegenerative diseases such as Alzheimer's disease.
European Patent No. EP1175901 discloses a method of promoting binding of a peroxisome proliferator-activated receptor to a target gene sequence and promoting gene expression downstream thereof by administering a peroxisome proliferator-activated receptor agonist. The agonist is a conjugated unsaturated fatty acids having 10 to 26 carbon atoms and containing a conjugated trienoic or a conjugated tetraenoic structure and salts and ester derivatives thereof, an example being punicic acid. Particularly, the patent discloses use of the method for reduction of visceral fat amount or suppression of visceral fat accumulation, prevention or amelioration of lipid metabolism abnormalities, prevention or amelioration of glucose metabolism abnormalities, or prevention or treatment of cancer can be carried out in the human or animal.
U.S. Application Publication No. 20110065662 discloses compounds, extracts and compositions thereof, and methods of using the same, to treat neurodegenerative disorders and/or improve brain health. In certain embodiments, said compounds are pomegranate flavonoids.
The therapeutic use of pomegranate oil or its derivative is still limited due to relatively high amounts of crude oil that should be consumed. In addition, many beneficial effects of pomegranate oil have been demonstrate only in in vitro cell culture models, due to the insufficient availability of orally administered oil.
Progression of neurodegenerative disease is associated with irreversible death of brain cells. Thus, there is a clear unmet need not only for a treatment after diagnosis but also for prevention means in cases where susceptibility can be identified in advance. There is further unmeet need for efficacious delivery means of pomegranate oils and derivative thereof to exert their therapeutic effects.